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Rare Artery Disease Linked to Gene Variant

Scientists have discovered a genetic cause for a rare disorder
that leads to calcium deposits in arteries in the lower half of
the body and in the joints of patients' hands and feet. The culprit
is a mutation in the gene encoding CD73, a protein that normally
helps to prevent calcium buildup. The researchers hope that understanding
the basis for this disease, which they call arterial calcification
due to deficiency of CD73 (ACDC), will help them find a cure.

An X-ray of a knee from a patient with ACDC,
showing calcium buildup in the artery. Courtesy of NHGRI.

Currently, 9 patients are known to have ACDC, and all come from
3 families. The patients experienced pain in their buttocks, legs
and joints, but doctors could find no signs of rheumatoid arthritis
or other recognized problems that might cause the symptoms. A research
team that included scientists from NIH’s National Heart,
Lung and Blood Institute (NHLBI) and National Human Genome Research
Institute (NHGRI) examined members of 2 affected families to search
for a common thread.

MRI and X-rays showed that members of the 2 families all had calcium
buildup in arteries in the lower half of their bodies, but not
around their hearts. In one family, 5 siblings but neither parent
was affected by the disorder. The researchers suspected that symptoms
might be due to a recessive gene variant. Recessive variants only
show their effects when found in both copies of the gene.

To test this theory, the team, led by Dr. William Gahl of NHGRI,
compared DNA from the parents of the family to their children's.
They found a region of DNA that was present only once in the parents,
but twice in the children. The team then compared this region to
the same region in 200 unaffected people. The results were published
on February 3, 2011, in the New England Journal of Medicine.

The researchers found a variant in a gene called NT5E that unaffected
people didn’t have. NT5E makes a protein called CD73, which
produces a small molecule called adenosine that helps regulate
many processes in the body.

The NHLBI team, led by Dr. Manfred Boehm and Dr. Cynthia St. Hilaire,
cultured the patients’ cells to examine the effects of the
mutation on an enzyme called TNAP (tissue-nonspecific alkaline
phosphatase). TNAP is known to degrade a calcium buildup inhibitor
and thus contribute to calcium deposits. The researchers found
that the mutant cells produced higher levels of TNAP. Adding adenosine
to the cell cultures restored normal levels of TNAP. In addition,
while mutant cells made more calcium phosphate crystals in culture,
restoring CD73 expression in the cells prevented crystal formation.

"Vascular calcification often results from poor diet and
lack of exercise," says Gahl, who is NHGRI clinical director
and director of the NIH Undiagnosed Diseases Program. "The
calcium buildup in arteries of our patients, however, arises because
the systems to inhibit it are not working in their cells. We hope
that an understanding of this faulty mechanism will guide us in
providing helpful treatments for these patients."